b cell lymphoma survival rate | Clinical support updates in Mantle Cell Lymphoma

Clinical support updates in Mantle Cell Lymphoma
Clinical support updates in Mantle Cell Lymphoma




Mantle lymphoma is an aggressive B-cell non-Hodgkin's lymphoma that is often considered incurable. Different clinical and biological biomarkers can be used to classify this lymphoma into different levels of risk. Several randomized trials reported in 2015 have highlighted optimal induction therapy. Recent advances include: (1) identifying new pathways to Target, (2) New therapies to treat relapse/refractory patients, and (3) monitoring of the minimal residual disease and the adoption of a therapy approach Maintenance to prevent relapses after induction or post stem cell transplant. Through clinical translation/research efforts, the overall survival of patients with mantle cell lymphoma has increased and should continue to improve.

Introduction
Cellular mantle lymphoma (MCL), an aggressive B-cell non-Hodgkin's lymphoma, is considered incurable. It accounts for about 4% of the lymphomas in the United States [1]. The median age at the time of presentation of the disease is approximately 60 years, and there is a predominantly male provision. The majority of patients present an advanced disease involving bone marrow and peripheral blood, as well as diffuse lymphadenopathy. Some patients also present a splenomegaly and extranodal diseases such as the lymphomateuse polypose of the large intestine. [2] Inflammatory or Lymphoma-associated symptoms such as fever, chills and nocturnal sweats are common. The diagnosis is based on the biopsy of a lymph node or bone marrow showing monomorphic leaves, small to medium lymphoid cells. [3] There are four cytological variants, including small cells, mantle area, diffuse, and blastic variant. [4] The pathognomonic characteristic of MCL is the overexpression of cyclin D1 because of chromosomal translocation t (11; 14) (q13; q32)., a phenomenon observed in more than 95% of cases [4] This determination can be made by immunohistochemistry or Fluorescence analysis by in situ hybridization. In cases where the cyclin D1 is not overexpressed, the cyclin D2 and D3 overexpression can be found [5]. The initial assessment of patients should include full blood count (CBC); Complete Chemistry Profile dehydrogenase (LDH) lactate levels; bone marrow biopsy; and a neck scan, chest, abdomen and pelvis-or 18-fluorodeoxyglucose positron emission tomography (PET)/CT. Endoscopic evaluation of the gastrointestinal tract should be considered, especially if the patient has clinical symptoms or anemia.

Clinical presentation
At 54 years old, the man presented to a primary care office with a lump on the right side of his neck. He indicated that the mass had existed for 2 months, and said he had a fever, shivers and night sweats for the past month. After examining the patient, the primary care physician found straight swollen lymph nodes, bilateral lymphadenopathy axillary, and right inguinal enlarged lymph nodes. In addition, the CBC showed an increase in white blood cells (WBC), with lymphocytosis and several unclassified cells. Results of pathology of a central right-hand biopsy of the patient's axillary ganglion have shown the Blastic variant type of MCL. The patient was then referred to a hematologist, who performed a FDG-PET scan. The analysis showed an increase standardized uptake value, as well as discrete masses in the right cervical region of the neck, bilateral lymphadenopathy axillary, lymphadenopathy retroperitoneal, absorption increased in the spleen, and Lymphadenopathy inguinal right. A bone marrow biopsy revealed the involvement of MCL. Peripheral blood was subjected to flow cytometry and Immunophenotyping showed a phenotype that was CD19. CD20-. and CD51-positive and CD10-. CD23-. and negative BCL6. This patient was diagnosed with the IVB MCL stage.

Clinical Management
Unlike other types of lymphoma, the treatment of MCL is generally not defined by Ann Arbor staging, since the majority of patients present an advanced disease. As a general rule, the treatment of newly diagnosed MCL can be adapted to younger patients (or those who are 65 years old who can tolerate intensive chemotherapy) and older patients (or those who are GT; 65 years who are not eligible for High dose therapy). Clinical and biological prognostic factors should also be taken into consideration when deciding on the timing of therapy and who the treatment regimen to use.

Prognostic factors
Mantle Cells International prognostic Index (MIPI). The MIPI was formulated by the Mantle Cell Lymphoma European Network; It uses age, the status Eastern Cooperative Oncology Group performance, LDH, and WBC count to stratify patients into three different risk groups. [6] Low-risk patients tend to do well, with a median duration of overall survival (bone) after diagnosis not reached and a 5-year bone rate of 60%. Intermediate-risk patients have a median operating system of 51 months, and high-risk patients have a median overall survival of 29 months. This index was validated by other groups, and the variations were used in retrospective and prospective trials. [7] In addition to the MIPI, the Biomarkers SOX11, Ki-67, p53. And P16 was also shown to have a prognostic value. SOX11 is a transcription factor, and its absence has been associated with a indolent form of MCL. [8] High proliferation Ki-67 and removal of p53 and p16 were found to be associated with the Blastic MCL variant, which has a bad result of the bone [9]. Profiling of gene expression (GEP) has identified preliminary molecular predictors. A recent study has identified RAN, MYC, TNFRSF10B, POLE2. and SLC29A2 as predictive factors for survival in a small series of patients with MCL. [10] Patients with an increased expression of all five genes had lower survival. Since GEP is not practical to occur on a large scale, this method needs to be explored more before it can be applied in clinical management. Although the genetic characteristic of the cyclin D1 MCL is due to the overexpression T (11; 14), a translocation, a differential overexpression of the D1 cyclin can be seen in the different samples of patients. Wiestner and Al identified patients with a cyclin D1 Region 3 ' untranslated truncated as having inferior results. [11] This may be due to modified MiR-16-1 regulation, as shown by Chen et al. 12

Upfront Treatment

For younger patients fit with MCL, the therapeutic strategy was to use aggressive induction chemotherapy followed by an autologous stem cell transplant (ASCT). The advantage of ASCT consolidation for has been demonstrated by the European Mantle cell of network lymphoma. Their study compared ASCT against consolidation for the maintenance treatment with interferon, and showed better progression-free survival (PFS) in the ASCT arm (median PFS, 39 vs. 17 months; P = 0.0108). [13] Although the role of ASCT in younger patients with MCL is clear, optimal induction chemotherapy has not been defined. Romaguera et al reported the results of the rituximab (R) regimen-HyperCVAD at the University of Texas MD Anderson Cancer Center. [14] This multi-agent diet contains hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose cytarabine and methotrexate for 6 to 8 cycles. The complete response (CR) The rate was 87% and the overall response rate (ORR) was 97%, with a 3-year survival rate without failure of 64% and the rate of 82% OS. [14] However, the results are not quite as favorable when tested in a multi-centric framework, with an ORR of 86%, a 55% CR rate, and a 66% PFS rate of about 3 years. [15] In addition, 90% of patients had grade 4 hematological toxicity, and only 61% of patients could complete the full treatment cycle. [15] Other alternatives to R-HyperCVAD include the Northern Diet (R-Maxi-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] in alternation with high-dose cytarabine without methotrexate). Geisler et al showed that this induction followed by ASCT gave a 6-year PFS rate of 66% and the rate of 70% OS. [16] Delarue et al developed a diet comprising 3 R-CHOP cycles followed by 3 cycles of R-Ptwi (rituximab, dexamethasone, high-dose cytarabine, and cisplatin), followed by ASCT. [17] The reported results are very promising, with a CR rate of 57%, ORR of 93%, and the 5-year bone rate of 75%. A recent Oncology Group Southwest (SWOG)-LED American Intergroup test in relation to R-Bendamustine (RB), followed by ASCT vs R-HyperCVAD followed by autografting in younger patients with untreated MCL. The results were reported in June 2015 at the 13th International Conference on the Malignant Lymphoma in Lugano, Switzerland [18] and updated to 2015 American Society of Hematology (ASH) Annual meeting. [19] It has been shown that although the treatment with RB vs R-HyperCVAD has been associated with the same ORR, CR, 2 years PFS, and bone levels, patients who received R-HyperCVAD had significantly more cases of myelosuppression, including anemia (59% vs. 9% with RB) , neutropenia (65% versus 34%, respectively), and thrombocytopenia (71% vs. 17%, respectively). R-HyperCVAD also resulted in more stem cell collection failures (29% vs 6%), and its use led to the early closure of the study. At this time, there is no clear evidence to show that diet induction should be the standard of care in younger patients with MCL. However, the most appropriate strategy may be to choose the diet associated with a high CR rate while sparing patients from the toxicity of the treatment so that they can access eligibility to ASCT.

As far as elderly patients who cannot tolerate chemotherapy or intensive ASCT, there are a number of options. Historically, R-CHOP chemotherapy has been used, with an ORR of 96%, a rate of 48% CR, [20] and a PFS duration of about 17 months. R-CHOP was also shown to be superior to R-FC (Fludarabine and Cyclophosphamide) by a group in Germany. In this study, the 4-year bone rate was 65% for R-CHOP vs. 50% for R-FC. [21] A recent study comparing R-CHOP vs VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) showed an improvement of 59% of the SSP in favour of VR-CAP, and the median overall survival rate was not reached vs. 56.3% with R-CHOP. [22] Another option in addition to the R-CHOP-based therapy is the use of bendamustine. Rummel et al studied the combination of RB in patients with untreated MCL, an ORR ratio of 75% and a CR rate of 50%, with secondary hematologic toxicity [23]. This diet was then compared to R-Chop in a large randomized non-inferiority trial in Europe, which showed srrb similar to those obtained with R-Chop (93% vs. 91%), as well as comparable CR rates (40% vs. 30%); However, RB-treated patients improved the median SSP (70 vs. 31 months), less hematological toxicity (30% vs. 68%), and fewer infections (37% vs. 50%). [23] As a result of recent studies, many physicians choose to use RB or VR-CAP rather than R-CHOP. Given that older patients are not eligible to undergo ASCT, the role of maintenance therapy was assessed after induction. The study by Germany that compared R-CHOP vs R-FC also evaluated the role of maintenance rituximab vs interferon. The researchers found that the arm of the study with the best PFS and OS was R-CHOP followed by rituximab maintenance, with a 4-year bone rate of 87%. [21] The role of rituximab maintenance was further confirmed by the meta-analysis of three major randomized trials showing an improvement in PFS with rituximab (relative risk [RR], 0.60 [CI 95%, 0.44 to 0.82]). [24] Although no study evaluated the role of rituximab maintenance after RB or VR-CAP, most physicians administering the maintenance treatment of patients regardless of the type of induction regimen used.

In addition to combined chemotherapy induction treatments, another option exists for elderly patients who may choose not to undergo multi-agent chemotherapy. Ruan et al studied lenalidomide rituximab as the initial treatment of MCL. This unique multi-center Test arm showed a 92% ORR, a 64% CR rate, and a 2 year PFS rate of 85%. [25] Patients were treated with this regimen for at least 36 cycles or until progression of the disease. Although this was not a randomized trial comparing lenalidomide rituximab vs. multi-agent chemotherapy, the ORR and PFS are certainly in tandem with historical controls. Table 1 presents a list of the induction treatments discussed.

A small number of patients with MCL have a indolent disease. Martin et al evaluated the watch-and-wait approach (similar to that followed in the management of patients with follicular lymphoma) for patients with asymptomatic disease or those with low MIPI, or for elderly patients with of MCL. The results show that the median duration of treatment was about 12 months (extremes, 4-128 months), [26] and the survival profile of the observation group appeared to be improved compared to that of the early treatment group. The majority of patients received R-CHOP-like treatment at time induction therapy was given. This result suggests that the watch-and-wait approach may be appropriate for a subset of patients with very indolent disease.

The patient in our initial case presentation received 6 cycles of RB followed by ASCT. He also enrolled in our trial using Rituximab plus bortezomib as a maintenance treatment after autografting. He is currently doing well and still in remission.

Recurrent disease

Prior to recent advances in new therapeutic products, patients who have relapsed MCL have been treated with multi-agent chemotherapy recovery, much like the treatment of diffuse large B-cell lymphoma (LMNH), with diets such as As Rice (rituximab, ifosfamide, carboplatin and Etoposide), R-ESHAP (rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), R-Ptwi, or strategies based on gemcitabine. RB was used as part of the relapsing disease and was combined with Cytarabine (R-BAC). The ORR of these agents appears to be high at 80% to 90%, with a CR rate of 60% to 70%. [27.28] However, adverse events are common, including cytopenias.

A variety of new therapies have been tested in recent years and have shown an efficacy in relapse MCL. Bortezomib, a proteasome inhibitor, demonstrated an ORR of 33% and a CR rate of 8% in this context, with the most common grade 3 or higher toxicity being peripheral sensory neuropathy in 13% of patients [29]. Temsirolimus, a mammalian target of rapamycin (MTOR) inhibitor, gave an ORR of 41% and a CR rate of 4% in a phase II study of patients who had relapsed MCL/refractory. [30] Patients treated with immunomodulator agent Lenalidomide were shown in a phase II trial to have an ORR of 35%, a 12% CR rate, and a 9-month median PFS. [31] Wang et al combined lenalidomide with rituximab as part of an MCL relapse and found that the plan resulted in an ORR of 58% and a CR rate of 33%. [32] Perhaps the most exciting agent to get approval from the U.S. Food and Drug Administration in this framework is the Ibrutinib tyrosine kinase inhibitor. [33] It has been shown to reach a 68% ORR and a 21% CR rate in patients who have relapsed MCL/refractory. These results are similar to the reported results for patients with MCL who received the bortezomib before vs those who did not, indicating that Ibrutinib is making a response in bortezomib resistant patients. The median duration of the response was 17.5 months, the PFS 2-year rate was 31%, and the 2-year bone rate was 47%. Overall, Ibrutinib was well tolerated; 16% of patients had grade 3/4 hematological toxicity and 44% had grade 1/2 diarrhea. [34] Although the approval of Ibrutinib has benefited many patients with MCL, it has become clear with a long-term follow-up that these patients may still experience progression of the disease during treatment. The median SSP is 13 months. [35]

Phosphoinositide 3 (cu. ft.) kinase inhibitors represent another class of drugs that have been studied in MCL/refractory relapse. In a phase I study, IDÉLALISIB, which, as Ibrutinib targets the B cell receptor pathway, generated 40% ORR, a 5% CR rate, and a median 3-month duration of the response. [36] At the ASH annual Meeting 2015, the results were presented from a phase I study venetoclax, a drug that generated some excitement in this setting. Gerecitano and Al Venetoclax evaluated, a B 2 cell lymphoma inhibitor, in patients who have relapsed/refractory MCL, follicular lymphoma, chronic lymphoid leukemia, and DLBCL [37]. Patients with relapse/refractory MCL appeared to have ORR more favorable at 75%, with a rate of 21% CR. We look forward to the end of this trial and the phase II trial in patients with MCL. In City of Hope, we will evaluate the combination of Ibrutinib and venetoclax in patients who have relapsed disease/refractory. Table 2 presents a list of new therapeutic products used in MCL/refractory relapse.